The sansalvamide A (San A) scaffold is a promising structure for the development of novel cancer therapeutics. We have used the San A scaffold to produce 7 compounds that are cytotoxic to pancreatic and colon cancer cell lines at nanomolar concentrations. The San A derivatives are of particular interest because they do not share structural homology with other classes of marketed cancer therapeutics, they appear to inhibit an established target (Hsp90) at a novel site, and they are significantly more potent than the drugs currently available for the treatment of colon and pancreatic cancer. Known Hsp90 inhibitors interact with the N-terminal domain whereas our compounds are unique in that they target the C-terminal domain and block the binding of inositol hexakisphosphate kinase 2 (IP6K2). It is the overall goal of this project to develop a novel chemotherapeutic agent based on the San A scaffold. It is our hypothesis that analogs of San A with even greater potency and selectively can be synthesized by modifying key structural features identified in our preliminary studies. The specific aims are to: a) Identify the binding site at the C-terminus of Hsp90 and design a potent second-generation lead candidate compound, b) Identify the key cellular targets and their role in San A's cytotoxic effect, and c) Identify the key cellular targets and their role in San A's cytotoxic effect. PUBLIC HEALTH RELEVANCE: Cancers have continued to evolve new mechanisms of action that make them resistant to most known chemotherapeutic agents. Consequently, there remains a serious and immediate need for the development of antitumor agents that target drug-resistant cancers. The goal of this project involves using conformational based design to synthesize potent new anticancer agents that act via binding to the C-terminus of Hsp90 thus inhibiting the binding of inositol hexakisphosphate kinase 2 (IP6K2). Current lead compounds show promise for binding to this novel site and show potent cytotoxicity (nanomolar) as well as differential selectivity for cancer over normal cells. Through the proposed structural studies of our lead compounds with their biological targets combined with synthesis and in vivo studies, we anticipate generating a new class of therapeutic agents that may be useful in treating cancers.